The overall goal of our research is to identify genetic factors that are necessary for the normal development and function of the eye. These factors are identified by a combination of genetic and molecular approaches in mice, where mutations lead to retinopathies. Once the molecular basis of the retinal disease is identified, the availability of the mouse model allows the intensive investigation of the role of the gene in normal and pathophysiologic states. The focus of this proposal is the mouse model, retinal degeneration 6. rd6 represents a unique model that shares phenotypes that are characteristic of flecked retinal disorders in humans (i.e. fundus flavimaculatus or retinitis punctata albescens). Fundal examination of mice homozygous for rd6 shows discrete dots or linear lesions distributed across the retina. Histological examination shows that the normal architecture of the retina is disrupted with folds and pseudorosettes. These focal areas of disorganization appear to correspond to abnormalities in the retinal pigmented epithelium, especially in later stages of the disease. Photoreceptor cells progressively degenerate and an abnormal electroretinogram is observed by five months of age. In addition, as observed with many human ocular disorders, the phenotypic expression of rd6 can be modified significantly. We have observed both suppression and increased severity of the rd6 phenotype within our crosses. Placing rd6 on different genetic backgrounds, therefore, offers the rare opportunity to dissect the genetic basis for phenotypic variability. In this application, we propose (1) to positionally clone rd6, (2) to map the genetic factors that interact with rd6 to delay or suppress its expression as well as those that cause increased disease severity, (3) to construct congenic lines to characterize these factors further, and (4) to examine the pathology of the mutation in the developing and adult eye and to identify pre-clinical alterations (i.e. primary lesions). Identification of disease causing genes and animal models is extremely important. Many eye diseases in humans, if identified early enough, can be treated to attenuate the disease process. If no treatment is currently available, knowing the molecular basis of the disease may provide insights leading to new treatment regimens and the models can then be used to test those therapeutics. The eventual identification of the genetic suppressor of rd6, for example, may provide a blueprint for a treatment for flecked retinal disorders. Finally knowledge of the disease causing genes may lead to an understanding of pathways that are critical in maintaining normal function and physiology of the eye and perhaps, may identify therapeutic targets for prevention of vision loss.